United Kingdom experience with alendronate and oesophageal reactions.

Alendronate is indicated for the treatment of osteoporosis in post-menopausal women. Although the drug has been associated with reports of severe oesophagitis, there have been no studies establishing the incidence of such reactions. Information was collected on 1523 patients included in a study conducted by means of prescription-event monitoring. Dyspepsia, nausea/vomiting, and abdominal pain were the most frequently reported events in the first month of treatment. After follow-up, 20 patients (1.3%) experienced oesophageal events that were considered to be possibly related to alendronate.

Newer antidepressants: a comparison of tolerability in general practice.

BACKGROUND: An increasing number of antidepressants have been released on the United Kingdom market in recent years, and these are being prescribed more frequently in general practice. Clinical trials suggest that such agents have similar efficacy and the choice of drug is probably based on tolerability, toxicity in overdose, and cost. AIM: To compare the tolerability and safety profile of six, newly marketed antidepressants used in general practice. METHOD: Studies have been conducted for six antidepressants: fluoxetine, sertraline, paroxetine, moclobemide, venlafaxine, and nefazodone, using the technique of prescription-event monitoring. Patients were identified using incident dispensed prescription data. Questionnaires were sent to patients' general practitioners six months after the date of first prescription. Questionnaires asked for date of birth, sex, indication for prescribing each drug, and all events entered in the patients' records after the date of first prescription. RESULTS: Each cohort exceeded 10,000 patients. Nausea/vomiting was the most frequently reported event for all drugs. The difference in incidence rates for drowsiness/sedation, male sexual dysfunction, and hypertension is shown. Mortality data are also reported. CONCLUSION: Frequently reported events were similar for all six drugs but there were clinically and statistically significant differences for less frequently reported events. The adjusted mortality rate was identical between the six drugs. This study provides valuable comparative data for six, widely used antidepressants in general practice.

Cohort study on calcium channel blockers, other cardiovascular agents, and the prevalence of depression.

AIMS: Some reports have suggested that calcium channel blockers may be associated with an increased incidence of depression or suicide. There is a paucity of evidence from large scale studies. The aim of this study was to assess rates of depression with calcium channel antagonists using data from prescription event monitoring studies. METHODS: Observational studies on large cohorts of patients using lisinopril, enalapril (ACE inhibitors), nicardipine (type 2 calcium channel blocker) and diltiazem (type 3 calcium channel blocker) were conducted, using prescription-event monitoring. Rates of depression in the different drugs and rate ratios (95% CI) were computed. RESULTS: The crude overall rates of depression during treatment were 1.89, 1.92 and 1.62 per 1000 patient months for the ACE inhibitors, diltiazem and nicardipine, respectively. Using the ACE inhibitors as the reference group, the rate ratios for depression were 1.07 (0. 82-1.40) and 0.86 (0.69-1.08) for diltiazem and nicardipine, respectively. CONCLUSIONS: This study does not support the hypothesis that calcium channel blockers are associated with depression, when considering patients treated in general practice in the UK.

Risk of non-fatal cardiac failure and ischaemic heart disease with long acting beta 2 agonists.

BACKGROUND: The long term safety of beta agonists, particularly in patients with heart disease, has not been fully established. METHODS: This study accessed the results of three cohort studies involving: 12,294 patients receiving at least one prescription for nedocromil between November 1986 and September 1988; 15,407 patients prescribed salmeterol between December 1990 and May 1991; and 8098 patients prescribed bambuterol between February 1993 and December 1995. Details of all dispensed prescriptions for these drugs prescribed by general practitioners in England soon after their launch were provided in confidence by the Prescription Pricing Authority. Questionnaires were sent to the prescriber asking for details of events occurring after the first prescription (prescription event monitoring). Rates and relative risks of non-fatal cardiac failure and ischaemic heart disease were calculated, comparing bambuterol and salmeterol with the reference drug nedocromil. RESULTS: The age and sex adjusted relative risk of non-fatal cardiac failure associated with bambuterol was 3.41 (95% confidence limits (CL) 1.99 to 5.86) when compared with nedocromil. When salmeterol was compared with nedocromil the adjusted relative risk of non-fatal cardiac failure was 1.10 (95% CL 0.63 to 1.91). The adjusted relative risk of non-fatal ischaemic heart disease was 1.23 (95% CL 0.73 to 2.08) and 1.07 (95% CL 0.69 to 1.66) for bambuterol and salmeterol, compared with nedocromil, respectively. However, in the first month of exposure the adjusted relative risk of non-fatal ischaemic heart disease was 3.95 (95% CL 1.38 to 11.31) when bambuterol was compared with nedocromil. CONCLUSIONS: Caution should be exercised when prescribing long acting oral beta agonists to patients at risk of cardiac failure. More definitive evidence would come from prospective randomised trials.

Nefazodone in community use: the results of prescription-event monitoring.

PURPOSE: This study was a pharmacovigilance exercise which aimed to determine the post-marketing event profile of nefazodone, a newly marketed antidepressant, in community use. METHODS: Information was collected on patients included in a non-interventional observational cohort study conducted by means of Prescription-Event Monitoring in England. Incidence densities were calculated for all reported events. RESULTS: Information was obtained for 11 834 patients. Nausea and dizziness were the most frequent adverse events that led to stopping nefazodone and the most frequently reported events during the first month of treatment. Unsteadiness and falls were reported more frequently in the elderly. Hepatic events, involuntary movements, thrombocytopenia, hallucinations and withdrawal reactions were reported rarely but were possibly associated with nefazodone. Eight overdoses involving nefazodone alone were reported with no serious clinical sequelae. Two premature births, one low birth weight term baby and two babies with renal abnormalities were outcomes in 38 pregnancies exposed in the first trimester to nefazodone. One death in a woman aged 71 years followed an illness with serotonergic features. CONCLUSIONS: Event data are presented for patients dispensed nefazodone in the community. The findings are discussed.

Is the incidence of upper respiratory tract infection independent of drug treatment in large cohort studies of longer term use drugs?

In observational cohort studies which monitor drug safety, the patterns of reported events are likely to be influenced by a number of factors. We hypothesized that the distribution of events which are unlikely to be adverse events associated with drug use, differ from that for events which may be adverse drug reactions. In 39 individual Prescription-Event Monitoring (PEM) studies, the incidence rates for upper respiratory tract infections (URTI) and back pain, in the first month of treatment and in the subsequent 5 months, were compared to those for nausea/vomiting and malaise/lassitude. For URTI and back pain there was no statistically significant difference in the event rates between these time periods. This pattern may be characteristic of events which are independent of the disease being treated and are unlikely to be adverse events associated with drug use. However, for nausea/vomiting and malaise/lassitude, which can be adverse events associated with drug treatments, the event rates in the first month of treatment were significantly greater than in subsequent months. These observations confirm that doctors are reporting events irrespective of whether or not they suspect the event to be an adverse event associated with the drug. This provides a simple validation of the PEM methodology.

Safety of long-term lamotrigine in epilepsy.

PURPOSE: To examine the safety of lamotrigine (LTG) used in general practice to treat epilepsy. METHODS: Information was collected on 11,316 patients who were included in a noninterventional observational cohort study conducted by means of Prescription-Event Monitoring (PEM). A follow-up study provided information on the first 3,994 patients who had taken LTG for > or = 6 months. Incidence density (ID) measurements were used to rank the frequency of the reported events. RESULTS: Rash was the most frequently reported nonepileptiform event (ID, 19.7/1,000 patient-months) in the first month of treatment and resulted in LTG being stopped in 2% of the 11,316 patients. Rash was reported more frequently among children aged 2-12 years (ID, 29.4/1,000 patient-months) than adults. Other events associated with the use of LTG included headache, drowsiness, nausea, vomiting, malaise, and lassitude. Rare serious events possibly associated with LTG included 12 cases reported as Stevens-Johnson syndrome, four cases of neutropenia, three cases of thrombocytopenia, and two cases of disseminated intravascular coagulation. There were also individual cases of leucopenia, a meningitic reaction, acute renal failure, hepatotoxicity, and a "lupus-like" reaction possibly associated with the drug. No foetal abnormalities were specifically associated with the use of the drug in pregnancy. No death was attributed to LTG. CONCLUSIONS: Patients had severe epilepsy, inadequately controlled by other antiepileptic agents. The results of these two studies suggest that LTG is acceptably safe when used for the treatment of refractory epilepsy.

A comparison of fluvoxamine, fluoxetine, sertraline and paroxetine examined by observational cohort studies.

OBJECTIVE: To compare the safety and side-effect profiles of the four selective serotonin reuptake inhibitor antidepressants (SSRIs), fluvoxamine, fluoxetine, sertraline and paroxetine. METHODS: The results from four observational cohort studies of the four SSRIs were compared. Each of these studies was conducted by Prescription-Event Monitoring (PEM). The exposure data were derived from general practitioner (GP) prescriptions confidentially supplied by the Prescription Pricing Authority (PPA) in England. Outcome data were obtained from questionnaires (green forms) on which the prescribing doctor recorded event data. The main findings comprised demographic information, including patients' date of birth and sex; the indication for prescribing the monitored drug; the effectiveness of the drug as perceived by the GP; the reasons for stopping treatment and all events recorded during and after treatment. RESULTS: The final cohort for each of the four SSRIs exceeded 10,000 patients. The sex, age distributions and indications for prescribing the four SSRIs were very similar. Only 36% of the GPs expressing an opinion reported fluvoxamine as effective, compared with approximately 60% for fluoxetine, sertraline and paroxetine. Fluvoxamine was associated with a higher incidence of adverse events than the other three SSRIs. Nausea/vomiting was both the most frequent clinical reason for stopping all four SSRIs and the most frequently reported clinical event. Adverse events reported in patients aged 70 years and over were comparable with the events reported for the total cohorts. Differences were identified between the four SSRIs for less frequently reported adverse events. Withdrawal symptoms were significantly more frequent with paroxetine than the other three SSRIs. CONCLUSIONS: The data from the four studies were comparable in terms of age distribution, sex of patients and indication for prescribing the drugs. Fluvoxamine had a considerably higher incidence of side-effects associated with its use than the other three SSRIs. The side-effect profiles of the four SSRIs were comparable for frequently reported events. Important differences were identified between the four SSRIs in respect of less frequently reported events. This study suggests that fluvoxamine compares unfavourably with fluoxetine, sertraline and paroxetine, both in terms of reported effectiveness and the incidence of adverse events. Biases possibly affecting the comparisons involved in this study are unlikely to account for the observed differences between fluvoxamine and the other three SSRIs.

Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies.

AIMS: Little is known about the frequency with which suspected adverse drug reactions are seen by general practitioners after the prescription of newly marketed drugs. We investigated age and sex specific incidence rates of suspected adverse drug reactions recorded by general practitioners in England after the prescription of selected newly marketed drugs. METHODS: Information was collected from 48 national cohort studies of newly marketed drugs studied by prescription-event monitoring. Questionnaires were sent to prescribers asking for details of events and suspected adverse drug reactions recorded in the patients' notes occurring after the drugs were prescribed. RESULTS: During the 48 cohort studies, a total of 513608 patients were investigated, of which 221781 (43.2%) were males and 285862 (55.7%) were females. The overall incidence of suspected adverse drug reactions in males was 12.9 per 10000 patient-months of exposure (95% confidence limits 12.3 to 13.5), and in females was 20.6 per 10000 patient-months of exposure (95% confidence limits 19.9 to 21.3). The overall age-standardised relative risk of an adverse drug reaction in females compared with males was 1.6 (1.5-1.7). This sex difference was significant in all age groups above 19 years of age, and was relatively consistent across all age groups (chi2 test for heterogeneity = 9.2, P=0.3). The highest rate of recording in males was in the 50-59 year age group, and in females was in the 30-39 year age group. CONCLUSIONS: In general practice in England, suspected adverse drug reactions to newly marketed drugs are recorded more often in adults aged between 30 and 59 years of age and are 60% more common in women than in men. The sex difference occurs in all age groups over 19 years of age.